A Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Participants With Active Psoriatic Arthritis

The ACR-50 is a composite measure defined as improvement of 50% from baseline in both the number of tender (68) and number of swollen (66) joints, and a 50% improvement in at least three of the following five criteria: PGA-PsA (VAS where, 0 is 'very good, no symptoms' and 100 is 'very poor, severe symptoms'), PhGA-PsA [(VAS) where 0=no disease activity and 100=maximum disease activity], PGAAP [(VAS) where 0=no pain \& 100=most severe pain], disability history questionnaire (i.e., HAQ-DI) [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do] and an acute phase reactant [i.e., erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)]. Percentages are rounded off to the nearest decimal.

The ACR-70 is a composite measure defined as improvement of 70% from baseline in both the number of tender (68) and number of swollen (66) joints, and a 70% improvement in at least three of the following five criteria: PGA-PsA (VAS where, 0 is 'very good, no symptoms' and 100 is 'very poor, severe symptoms'), PhGA-PsA [(VAS) where 0=no disease activity and 100=maximum disease activity], PGAAP [(VAS) where 0=no pain \& 100=most severe pain], disability history questionnaire (i.e., HAQ-DI) [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do] and an acute phase reactant (i.e., ESR or CRP). Percentages are rounded off to the nearest decimal.

The TJC 68 is a total score of points assigned for the presence of tenderness in the 68 joints in the upper body and upper/lower extremity. The response to tenderness for each joint was evaluated using the following scale: 'Present' was assigned a score of 1 whereas, 'Absent', 'Not Done', 'Not Applicable', or joints with missing response were assigned a score of 0. The sum of all tender joints was derived. The overall tender joint count ranged from 0 to 68, with a higher score indicating a greater degree of tenderness. A negative change from baseline indicates improvement.

The SJC 66 (TJC 68 joint assessment minus hip joints, which cannot be assessed for swelling) is a total score of points assigned for presence of swelling in the 66 joints in the upper body and upper/lower extremity. The response to swelling for each joint was evaluated using the following scale: 'Present' was assigned a score of 1 whereas, 'Absent', 'Not Done', 'Not Applicable', or joints with missing response were assigned a score of 0. The sum of all swollen joints was derived. The overall swollen joint count ranged from 0 to 66, with a higher score indicating a greater degree of swelling. A negative change from baseline indicates improvement.

Participants assessed their overall disease status based on symptoms of psoriasis and psoriatic arthritis at the time of the visit using the PGA-PsA VAS of 100 millimeters (mm) which ranges from 0 (very good, no symptoms) to 100 (very poor, severe symptoms). A negative change from Baseline indicates improvement in symptoms.

Participants assessed their overall psoriatic arthritis-related pain at the time of the visit using the PGAAP VAS of 100 mm which ranges from 0 (no pain) to 100 (most severe pain). A negative change from Baseline indicates improvement in pain.

The participants' overall disease status was assessed, taking into account signs, symptoms, and function, of all components of joint and skin affected at the time of the visit and this overall status was rated by the investigator using the PhGA-PsA VAS of 100 mm where 0 is 'very good, asymptomatic, and no limitation of normal activities' and 100 is 'very poor, very severe symptoms which are intolerable, and inability to carry out all normal activities'. A negative change from Baseline indicates improvement in symptoms.

The HAQ-DI consists of 20 questions referring to eight domains consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored from 0 (without any difficulty) to 3 (unable to do). The worst score within each domain will be used as the domain score (i.e., if the score for one question is 1 and 2 for the other, then the worst score for the domain is 2). The HAQ-DI total score is calculated by dividing the sum of the domain scores by the number of non-missing domains. The total score indicates the patient's self-assessed level of functional ability and higher scores indicate worse functional ability. The HAQ-DI total score ranges from 0 to 3. A higher score indicates worse function and greater disability. A negative change from Baseline indicates improved function.

Tender score (0 = no tenderness, 1 = tender, 2 = tender and wince, 3 = tender and withdraw) is collected for Dactylitis Assessments on the Dactylitis Score Sheet that is used for calculation of total score. DC equals the number of tender fingers and toes (tender score >0). For participants with dactylitis status absent for all the fingers and toes, the DC is set as 0. The total score range of DC is from 0 to 60, higher scores indicate greater presence of dactylitis. A negative change from baseline indicates improvement.

Enthesitis is assessed using LEI. The enthesitis examination by LEI evaluates the presence or absence of pain by applying local pressure on 6 anatomical sites: medial femoral condyle (left and right), lateral epicondyle (left and right), and the achilles tendon insertion (left and right). Enthesitis at each site is scored as 0 (enthesitis absent) and 1 (enthesitis present). LEI is derived as the sum of the enthesitis score over the 6 sites, divided by the number of sites with non-missing score. The total score ranges from 0 to 6, higher scores indicate greater degree of enthesitis. A negative change from baseline indicates improvement.

MDA is a measure to indicate a state of minimal disease activity, and is a composite score of 7 domains. A participant is considered as having achieved the MDA if the participant fulfills at least 5 of the following 7 criteria: TJC 68 ≤1; SJC 66 ≤1; Psoriasis area and severity index (PASI) score ≤1 [The total score ranges from 0 (no disease) to 72 (maximal disease)] or body surface area (BSA) ≤3%; PGAAP ≤15 [using VAS on a scale of 0 (no pain) to 100 (serious pain)]; PGA-PsA ≤20 [using VAS on a scale of 0 (very well) to 100 (very poor)]; HAQ-DI score ≤0.5; LEI score ≤1. Percentages are rounded off to the nearest decimal.

The DAPSA score is a composite score and was calculated using: TJC68, SJC66, PGA-PsA, PGAAP, and hsCRP level (milligram per deciliter [mg/dL]). DAPSA scores 0-4 = remission, 5-14 = low disease activity, 15-28 = moderate disease activity, and >28 = high disease activity. The DAPSA score has a lower bound of 0 and has no upper bound. A higher DAPSA score indicated more active disease activity. A negative change from baseline indicates improvement.

PASI-75 is assessed in participants with psoriasis involvement for ≥ 3% of the BSA at Baseline and assesses the extent of involvement and severity of psoriasis. To calculate the PASI, the body is divided into 4 regions: the head and neck, trunk, upper limbs, and lower limbs. Each of these areas are assessed separately for the percentage of the area involved and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4, which translates to a numeric score that ranges from 0 (indicates no involvement) to 6 (90% to 100% involvement). The PASI produces a numeric score that can range from 0 (no disease) to 72 (maximal disease). For PASI-75, the improvement threshold from baseline in PASI score is 75%. A higher score indicates more severe disease. Percentages are rounded off to the nearest decimal.

PhGA-PsO responder is defined as participants 1) who had PhGA-PsO score of 0 or 1 at any given post-baseline visit; and 2) who had at least 2-point improvement from baseline. The PhGA-PsO is measured using a 0 to 4 scale with a 0 meaning clear or a 4 meaning severe. The proportion of participants achieving PhGA-PsO response at Week 12 was calculated and analyzed for participants with a score of at least 2 at baseline. Percentages are rounded off to the nearest decimal.

Adverse Event(AE)=medical occurrence that does not necessarily have a causal relationship with this drug also including clinically meaningful findings in laboratory safety tests,vital signs,weight,and electrocardiogram(ECG).TEAEs=AEs occurring at time of or post study drug dosing until study end.SAE=any medical occurrence at any dose that resulted in death,was life-threatening,required inpatient hospitalization/prolongation of existing hospitalization,resulted in persistent or significant disability/incapacity,was a congenital abnormality/birth defect,an important medical event.AESIs included Common Terminology Criteria for Adverse Events(CTCAE)Grade≥2 cytopenia,CTCAE Grade≥3 elevation of creatine phosphokinase(CPK)[clinically significant or not]defined as CPK>5xupper limit of normal(ULN),infections,adverse events of abnormal liver function tests,adverse events of renal dysfunction,major adverse cardiovascular events,thromboembolic events,gastrointestinal perforation,and malignancies.

Plasma concentration of NDI-034858 was measured in participants who received low, medium, or high doses of NDI-034858.